The main goal of this project is to investigate whether dietary isoflavones such as genistein can inhibit prostate cancer growth through activation of tumor suppressor microRNAs (miRNAs) using both in vitro and in vivo models. Prostate cancer is the most common male malignancy and the second leading cause of cancer death among men in the United States. The rationale for this project is that recent studies have shown significant effects of diet on modulation of miRNAs using both in vitro and in vivo models. Based on our preliminary data and published literature, we hypothesize that genistein can activate a set of tumor suppressor miRNAs thereby inhibiting prostate cancer progression through two different pathways. First, genistein induced tumor suppressor miRNAs can repress oncogene expression by binding to the 3'untranslated region of mRNA (3'UTR). Second genistein induced tumor suppressor miRNAs can activate the transcription of tumor suppressor genes by binding to the 5'upstream region of the gene or activate translation by binding to the 5'untranslated region of mRNA (5'UTR). This project is novel and timely because the roles of genistein mediated activation of tumor suppressor miRNAs in the regulation of prostate cancer progression have not been investigated. We also hypothesize that the molecular mechanism of genistein's mediated activation of tumor suppressor miRNAs are through epigenetic pathways. These hypotheses will be tested by pursuing the following three specific aims.
Specific Aim # 1. To test the hypothesis that genistein mediated activation of tumor suppressor microRNAs are involved in the regulation of prostate cancer.
Specific Aim # 2: To test the hypothesis that DNA methylation and histone modifications are the key mechanisms of genistein mediated activation of microRNAs in prostate cancer.
Specific Aim # 3: To test the hypothesis that genistein can suppress prostate cancer growth in a nude mouse model through activation of microRNAs. Impact: The project will provide a novel paradigm with high impact in the field of management of prostate cancer since dietary mediated activation of tumor suppressor miRNAs and their roles in the inhibition of prostate cancer progression have never been investigated. Successful accomplishment of these experiments will provide novel strategies for the treatment of prostate cancer.

Public Health Relevance

Prostate cancer is the most common male malignancy and the second leading cause of cancer death among men in the United States. The rationale for this project is that recent studies have shown significant effects of diet on modulation of miRNAs using both in vitro and in vivo models. Based on our preliminary data and published literature, we hypothesize that genistein can activate a set of tumor suppressor miRNAs thereby inhibiting prostate cancer progression through different pathways. The major barrier to progress in the management of prostate cancer is the high toxicity of the drugs currently in use. The present proposal will address this problem by investigating the use of dietary methods for the management of prostate cancer in both in vitro and in vivo models. We have proposed a series of experiments to investigate the role of genistein in the regulation of prostate cancer progression through modulation of tumor suppressor miRNAs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160079-02
Application #
8298153
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Ross, Sharon A
Project Start
2011-07-06
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$459,367
Indirect Cost
$149,403
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Hirata, H; Hinoda, Y; Shahryari, V et al. (2014) Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells. Br J Cancer 110:1645-54
Saini, Sharanjot; Majid, Shahana; Shahryari, Varahram et al. (2014) Regulation of SRC kinases by microRNA-3607 located in a frequently deleted locus in prostate cancer. Mol Cancer Ther 13:1952-63
Majid, Shahana; Dar, Altaf A; Saini, Sharanjot et al. (2013) MicroRNA-23b functions as a tumor suppressor by regulating Zeb1 in bladder cancer. PLoS One 8:e67686
Chiyomaru, Takeshi; Yamamura, Soichiro; Fukuhara, Shinichiro et al. (2013) Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer. PLoS One 8:e58929
Hirata, H; Ueno, K; Nakajima, K et al. (2013) Genistein downregulates onco-miR-1260b and inhibits Wnt-signalling in renal cancer cells. Br J Cancer 108:2070-8
Ueno, K; Hirata, H; Shahryari, V et al. (2013) microRNA-183 is an oncogene targeting Dkk-3 and SMAD4 in prostate cancer. Br J Cancer 108:1659-67
Majid, Shahana; Dar, Altaf A; Saini, Sharanjot et al. (2013) miRNA-34b inhibits prostate cancer through demethylation, active chromatin modifications, and AKT pathways. Clin Cancer Res 19:73-84
Ueno, Koji; Hirata, Hiroshi; Hinoda, Yuji et al. (2013) Frizzled homolog proteins, microRNAs and Wnt signaling in cancer. Int J Cancer 132:1731-40
Chiyomaru, Takeshi; Yamamura, Soichiro; Fukuhara, Shinichiro et al. (2013) Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR. PLoS One 8:e70372
Hirata, Hiroshi; Ueno, Koji; Shahryari, Varahram et al. (2013) MicroRNA-182-5p promotes cell invasion and proliferation by down regulating FOXF2, RECK and MTSS1 genes in human prostate cancer. PLoS One 8:e55502

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